The term autoimmunity refers to physiologically normal immune processes against self-antigens. In rare cases, the regulatory mechanisms become deflective and the uncontrolled production of autoantibodies or activation of autoreactive T-cells can subsequently cause disease. Substances may be capable of evoking autoimmune disease, and it is a challenge in routine toxicology to recognize such substances. In in vivo toxicity studies, uncommon inflammation in exposed animals should be discussed in terms of non-immune toxicity (e.g. irritation), infection, allergy and autoimmunity, taking into account that a response in even a few animals may be significant. Moreover, early morphological indicators of inflammation and lymphoid organ alterations can direct further investigation.